The mechanisms involved in opiate tolerance and physical dependence development are under investigation. A hypothesis has been proposed for opiate action that is based on opiate-Ca++ interactions. Acute opiates effects are attributed to a lowering of neuronal Ca++ with consequent inhibition of neuronal activity resulting from a decrease in neurotransmitter release. Tolerance results from a counteradaptive response on the lowering of neuronal Ca++ and the consequence is Ca++ accumulation which antagonizes opiate effects (tolerance). The ability to retain Ca++ after frequent repeated opiate administration becomes dependent on the presence of the opiate (physical dependence) and discontinuance of the opiate results in increased cytosol Ca++ and neurotransmitter release and the withdrawal syndrome. To validate the hypothesis, studies on acute and chronic opiate administration on calcium flux are being carried out on synaptosomes, mast cells and red blood cells of the mouse and rat. Pharmacologic studies are also being performed on the isolated tissue or organ preparations such as the guinea pig ileum and the vas deferens of the mouse, rat and rabbit to define the importance of mu, kappa and delta receptors in tolerance and dependence.